Method of enhancing cellular production of molecular chaperon, hydroxylamine derivatives useful for enhancing the chaperon production and the preparation thereof

A method of increasing activity of a molecular chaperone in a eukaryotic cell that is exposed to a physiological stress comprising:

• treating the cell that is exposed to a physiological stress accompanying allergic diseases, immune diseases, autoimmune diseases, diseases of viral or bacterial origin, tumorous, skin and/or mucous diseases, epithelial disease of renal tubulus, atherosclerosis, coronarial disease, pulmonary hypertonia, cerebrovascular ischemia, stroke, or traumatic head injury, with an effective amount of a chemical compound to increase the activity of the molecular chaperone in the cell beyond the amount induced by the physiological stress, wherein the chemical compound is selected from hydroxylamine derivatives represented by formula (II),
• or a salt thereof or an optically active stereoisomer thereof,
• wherein A is an alkyl, substituted alkyl, aralkyl, aralkyl substituted in the aryl and/or alkyl moiety, aryl, substituted aryl, heteroaryl or substituted heteroaryl group,
• Z is a covalent bond, oxygen or ═NR3, wherein R3 is selected from the group consisting of hydrogen, an alkyl, substituted alkyl, aryl, substituted aryl, aralkyl group and an aralkyl group substituted in the aryl and/or alkyl moiety,
• R is an alkyl or substituted alkyl group,
• X is oxygen, an imino or substituted imino group, and
• R′ is hydrogen, an alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, aralkyl substituted in the aryl or alkyl moiety, acyl or substituted acyl group.

A method of treating a disease connected with the function of the chaperone system or associated with the injury of the membrane of a cell or cell organellum or preventing the same which comprises:

• administering to a host that has been exposed to a physiological stress accompanying allergic diseases, immune diseases, autoimmune diseases, diseases of viral or bacterial origin, tumorous, skin and/or mucous diseases, epithelial disease of renal tubulus, atherosclerosis, coronarial disease, pulmonary hypertonia, cerebrovascular ischemia, stroke, or traumatic head, injury an effective amount of a chemical compound to increase the expression of a molecular chaperone by cells of the host beyond an amount induced by the physiological stress to ameliorate the effect caused by the pathological condition in the organism, wherein the chemical compound is selected from hydroxylamine derivatives represented by formula (II),
• or a salt thereof or an optically active stereoisomer thereof, wherein
• A is an alkyl, substituted alkyl, aralkyl, aralkyl substituted in the aryl and/or alkyl moiety, aryl, substituted aryl, heteroaryl or substituted heteroaryl group,
• Z is a covalent bond, oxygen or ═NR3, wherein R3 is selected from the group consisting of hydrogen, an alkyl, substituted alkyl, aryl, substituted aryl, aralkyl and aralkyl substituted in the aryl and/or alkyl moiety,
• R is an alkyl or substituted alkyl, and
• X is oxygen, an imino or substituted imino group, and
• R′ is hydrogen, an alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, aralkyl having a substituted aryl or alkyl moiety, acyl or substituted acyl group.

A hydroxylamine derivatives of the formula (II)

• wherein
• a) X is oxygen,
• A is C1-20 straight or branched alkyl, unsubstituted or substituted aryl, unsubstituted or substituted aralkyl, naphtyl or N-containing heteroaromatic,
• Z is a chemical bond,
• R′ is H, C1-4 alkyl or aralkyl, and
• R is a group of the formula (b),
• where R5 and R6 are independently H, straight or branched alkyl, or cycloalkyl, or R5 and R6, when taken together with the N-atom adjacent thereto, form a 3- to 7-membered saturated heterocyclic ring, Y6 is H or —OH, k is 1, 2 or 3, and m is 1, 2, or 3, with the proviso that when A is other than alkyl and R′ is H, Y6 is H, or
• b) X is ═NR4, wherein R4 is H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, or unsubstituted or substituted aralkyl,
• A is unsubstituted or substituted aryl, or unsubstituted or substituted aralkyl, or cycloalkyl,
• Z is a chemical bond, oxygen or ═NR3, wherein R3 is H or unsubstituted or substituted alkyl,
• R′ is unsubstituted or substituted alkyl or unsubstituted or substituted aryl, or unsubstituted or substituted aralkyl, and
• R is a group of the formula (b), wherein R5 and R6 are independently H, straight or branched alkyl, or cycloalkyl, or R5 and R6, when taken together with the N-atom adjacent thereto, form a 3 to 7-membered saturated heterocyclic ring, Y6 is H or —OR7 wherein R7 is H, unsubstituted or substituted alkylcarbonyl, or arylcarbonyl, k is 1, 2 or 3, and m is 1, 2 or 3, or
• c) X is oxygen,
• A is unsubstituted or substituted alkyl, unsubstituted or substituted aralkyl,
• Z is oxygen,
• R′ is alkyl or aralkyl,
• R is a group of the formula (b), wherein R5 and R6 are independently H, straight or branched alkyl, or cycloalkyl, or R5 and R6, when taken together with the N-atom adjacent thereto, form a 3- to 7-membered saturated heterocyclic ring, Y6 is H or —OR7 wherein R7 is H, unsubstituted or substituted alkylcarbonyl, or arylcarbonyl, k is 1, 2 or 3, and m is 1, 2 or 3, or
• d) X is oxygen,
• Z is ═NH and
• A is unsubstituted or substituted alkyl, cycloalkyl, unsubstituted or substituted aralkyl, phenyl or phenyl substituted with halo, alkyl, haloalkyl, alkoxy or nitro,
• R′ is alkyl or aralkyl, and
• R is a group of the formula (b), wherein R5 and R6 are independently H, straight or branched alkyl, or cycloalkyl, or R5 and R6, when taken together with the N-atom adjacent thereto, form a 3- to 7-membered saturated heterocyclic ring, Y6 is H or —OH, k is 1, 2 or 3, and m is 1, 2 or 3.

A pharmaceutical composition comprising pharmaceutically acceptable carriers and auxiliaries, for the treatment of cardiovascular, vascular, cerebral, allergic, immune, or autoimmune diseases, diseases caused by viral or bacterial infections, tumorous, skin or mucosal diseases, wherein the said composition contains 0.5 to 99.5% by weight of a hydroxylamine compound of the formula (II)

• wherein
• a) X is oxygen,
• A is C1-20 straight or branched alkyl, unsubstituted or substituted aryl, unsubstituted or substituted aralkyl, naphtyl or N-containing heteroaromatic,
• Z is chemical bond,
• R is H, C1-4 alkyl or aralkyl, and
• R is a group of the formula (b),
• where R5 and R6 are independently H, straight or branched alkyl, or cycloalkyl, or R5 and R6, when taken together with the N-atom adjacent thereto, form a 3 to 7-membered saturated heterocyclic ring, Y6 is H or —OH, k is 1, 2 or 3, and m is 1, 2, or 3, with the proviso that when A is other than alkyl and R′ is H, Y6 is H, or
• b) X is ═NR4, wherein R4 is H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, or unsubstituted or substituted aralkyl,
• A is unsubstituted or substituted aryl, or unsubstituted or substituted aralkyl, or cycloalkyl,
• Z is a chemical bond, oxygen or ═NR3, wherein R3 is H or unsubstituted or substituted alkyl,
• R′ is unsubstituted or substituted alkyl, unsubstituted or substituted aryl, or unsubstituted or substituted aralkyl, and
• R is a group of the formula (b), wherein R5 and R6 are independently H, straight or branched alkyl, or cycloalkyl, or R5 and R6, when taken together with the N-atom adjacent thereto, form a 3- to 7-membered saturated heterocyclic ring, Y6 is H or —OR7 wherein R7 is H, unsubstituted or substituted alkylcarbonyl, or arylcarbonyl, k is 1, 2 or 3, and m is 1, 2 or 3, or
• c) X is oxygen,
• A is unsubstituted or substituted alkyl, unsubstituted or substituted aralkyl,
• Z is oxygen,
• R′ is alkyl or aralkyl,
• R is a group of the formula (b), wherein R5 and R6 are independently H, straight or branched alkyl, or cycloalkyl, or R5 and R6, when taken together with the N-atom adjacent thereto, form a 3- to 7-membered saturated heterocyclic ring, Y6 is H or —OR7 wherein R7 is H, unsubstituted or substituted alkylcarbonyl1 or arylcarbonyl, k is 1, 2 or 3, and m is 1, 2 or 3, or
• d) X is oxygen,
• Z is ═NH and
• A is unsubstituted or substituted alkyl, cycloalkyl, unsubstituted or substituted aralkyl, phenyl or phenyl substituted with halo, alkyl, haloalkyl, alkoxy or nitro,
• R′ is alkyl or aralkyl, and
• R is a group of the formula (b), wherein R5 and R6 are independently H, straight or branched alkyl, or cycloalkyl, or R5 and R6, when taken together with the N-atom adjacent thereto, form a 3- to 7-membered saturated heterocyclic ring, Y6 is H or —OH, k is 1, 2 or 3, and m is 1,2 or 3.